1. Field of the Invention
The present invention relates to use of compounds for treating cancer, and particularly to dihydropyrimidine derivatives for targeting cancer stem cells.
2. Description of the Related Art
Drug discovery programs for oncology typically select compounds which have a predilection for inducing cytotoxic effects in cancer cell lines versus non-cancer cells and for inhibiting the growth of transplanted cancer cells in the flanks of immunocompromised mice. Unfortunately, inducing cytotoxic effects in vitro and inhibition of tumor growth in vivo is not the end story for curing cancer in preclinical models. This is, at least in part, due to the presence of cancer stem cells (CSCs), a small sub-type of cells that are relatively resistant to therapy and able to repopulate in vivo. It is believed that tumors are organized in a cellular hierarchy driven by cancer stem cells (CSCs). The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of the tumor. This hypothesis has fundamental implications for oncology and clinical implications for the early detection, prevention, and treatment of cancer. There are now numerous studies which have identified cancer stem cells in leukemia, breast, brain, lung, colon, and other cancers. To cause relapse, CSCs must have survived primary treatment. A number of factors may be responsible for this survival of CSCs, including stem cell quiescence, protected niche environment, up-regulated expression of xenobiotic efflux pumps, enhanced anti-apoptotic and DNA repair pathways. The first identification of breast cancer stem cells was defined by the combined expression of cell surface markers CD44+/CD24−/low/lin−. As few as 200 of these cells generated tumors in NOD/SCID mice, whereas 20,000 cells that did not display this phenotype failed to generate tumors. Later, studies suggested that aldehyde dehydrogenase 1 (ALDH-1), a detoxifying enzyme responsible for oxidation of retinol to retinoic acid, may be a more potent marker of breast CSCs. ALDH-1-positive breast CSCs can induce tumor formation with as few as 500 cells. Breast cancer cells that expressed ALDH-1 were more likely to be estrogen receptor (ER) negative, progesterone receptor (PR) negative, and human-epidermal growth factor receptor type 2 (HER-2) positive, and frequently developed distant metastases. ALDH-1-positive cells are resistant to conventional chemotherapy with paclitaxel and epirubicin. Previous studies have shown that adult stem cells can be identified by a side population (SP) phenotype. A SP isolated from the breast cancer cell line MCF7 was found to represent small percentage of the total cell line and it contained the tumorigenic fraction, as demonstrated by transplantation experiments in NOD/SCID mice xenografts. This fraction was also able to reconstitute the initial heterogeneity of the cell line. In breast tumors, the use of neoadjuvant regimens showed that conventional chemotherapy could lead to enrichment in CSCs in treated patients as well as in xenografted mice. This suggests that many cancer therapies, while killing the bulk of tumor cells, may ultimately fail because they do not eliminate CSCs, which survive to regenerate new tumors. Thus, there remains an urgent need for new pharmaceutical compounds and compositions to effectively eradicate and target cancer stem cells.
ATP binding cassette (ABC) transporters form one of the largest transmembrane protein families. These proteins use cellular ATP to drive the transport of various substrates across cell membranes including drugs, metabolites and other compounds. Human ABCG2 is the second member of the G subfamily of ABC transporters. ABCG2 was first cloned from doxorubicin-resistant human MCF-7 breast cancer cells and named as breast cancer resistance protein (BCRP). ABCG2 is sharply down-regulated during hematopoietic stem cell differentiation and is expressed at a low level in mature cells compared with progenitor cells. The highly regulated expression of ABCG2 suggests that ABCG2 may play a regulatory role in maintaining stem cells in an undifferentiated state. A RNA interference approach showed that the suppression of ABCG2 could significantly inhibit cancer cell proliferation. Furthermore, the blocking of ABCG2 function by fumitremorgin C, a chemical inhibitor, also inhibited cell proliferation via the prolonged G0/G1 interval. These data suggest that ABCG2 may contribute to cancer cell proliferation. Taking into account that the SP phenotype is mainly mediated by ABCG2 and the conserved expression of ABCG2 in stem cells, it is conceivable that ABCG2 may serve as a novel biomarker of CSCs. Since ABCG2 functions as a high capacity transporter with a wide range of substrates including various chemotherapy drugs, it has been shown to participate in the multidrug resistance of tumors.
Thus, a method for treating cancer solving the aforementioned problems is desired.